The career development of physician-scientists requires a broad approach in preparation for a career in academic medicine with research, teaching, and clinical responsibilities. This grant proposes a four-year career development plan consisting primarily of targeted hypothesis-driven research, but also incorporating teaching and mentoring activities, participation in institutional and national conferences and meetings, and continued clinical training. The University of Wisconsin-Madison provides the ideal environment to develop a career as a physician-scientist, with a reputation for premiere medical care and cutting-edge biomedical research, state-of-the-art facilities, extensive technical and intellectual resources, and a strong tradition of open collaboration among researchers and clinicians. The proposed research will investigate the dynamic and complex host-pathogen interactions involved in viral replication and pathogenesis. The simple genomic structure of positive-strand RNA viruses and experimental evidence suggest that host factors are indispensable for their replication, although the identity of these host factors and their functional impact on viral replication remain largely unknown. The recent development of novel viral replication systems in the well-studied yeast Saccharomyces cerevisiae permits the functional investigation of the cellular host factors involved in positive-strand RNA virus replication. Flock house virus (FHV), a bipartite positive-strand RNA virus and member of the Nodaviridae family, is the only animal virus shown to replicate in S. cerevisiae, and consequently represents a unique model to investigate the mechanisms of viral replication. The S. cerevisiae experimental system will be used to isolate and characterize yeast mutants unable to support FHV replication. A concurrent immunochemical approach will also be used to isolate and characterize cellular host proteins associated with the FHV RNA polymerase. The identification and characterization of host-pathogen interactions, with a particular emphasis on the impact of cellular host factors, are crucial both to understand the basic mechanisms of viral replication and pathogenesis and to design rational antiviral therapies.